It is well known that a wide range of diseases are caused by retroviruses. As presently understood, acquired immunodeficiency syndrome (AIDS) is a disease of the immune system caused by the retrovirus HIV (Human Immunodeficiency Virus). According to estimates from the World Health Organization, AIDS affects millions of people and is continuing to spread. In virtually all cases, AIDS results in death of the infected individual.
Retroviruses HIV-1 and HIV-2 have been identified as a cause of AIDS. A retroviral protease, is a proteolytic enzyme that participates in the maturation of new infectious virions in infected cells during the reproductive cycle. In a number of retroviruses, for example, HIV-1 and HIV-2, each have a region in their genome that codes for a “gag-protease.” The “gag-protease” is responsible for the correct proteolytic cleavage of the precursor proteins that are produced from the genome regions coding for the “Group Specific Antigens” (gag).
The “gag-protease” cleaves the major core protein p24 of HIV-1 and HIV-2 preferentially N-terminally of proline residues, for example, in the divalent residues Phe-Pro, Leu-Pro, or Tyr-Pro. It is a protease having a catalytically active aspartate residue in the active center, i.e., an aspartate protease. During cleavage, the structural proteins of the virus core are liberated. The “gag-protease” itself is a component of a precursor protein encoded by the pol-genome region of HIV-1 and HIV-2, which also contain regions for the “reverse transcriptase” and “integrase” and is thought to be cleaved by autoproteolysis.
Retroviral protease is a critical enzyme in the retroviral replication process. Propagation of a retrovirus, such as HIV, can be impeded by exposing the virus to a retroviral protease inhibitor. As used herein, protease inhibitor refers to compounds that inhibit proteases of viral origin, and that are useful in the prophylaxis or treatment of viral infections caused by retroviruses, such as HIV, in mammals, both human and nonhuman. Protease inhibitors perform at the final stage of viral replication, and prevent HIV from making new copies of itself by interfering with the HIV protease enzyme. As a result, the new copies of HIV are not able to infect new cells.
Retroviral protease inhibition typically involves a transition-state mimetic whereby the retroviral protease is exposed to a compound that binds, typically in a reversible manner, to the enzyme in competition with the gag and gag-pol proteins to inhibit specific processing of structural proteins and the release of retroviral protease itself. In this manner, retroviral replication proteases can be effectively inhibited.
Several classes of compounds for inhibition of proteases, including HIV protease, have been proposed. Such compounds include hydroxyethylamine isosteres, reduced amide isosteres, and nonpeptide isosteres. See, for example, EP 0 346 847; EP 0 342 541; Roberts et al., “Rational Design of Peptide-Based Proteinase Inhibitors,” Science, 248, 358 (1990); Erickson et al., “Design Activity, and 2.8 Å Crystal Structure of a C2 Symmetric Inhibitor Complexed to HIV-1 Protease,” Science, 249, 527 (1990); and S. Thaisrivongs, “Structure-Based Design of Non-Peptide HIV Protease Inhibitors,” 35th Annual Buffalo Medicinal Chemistry Meeting, State University of New York at Buffalo, Buffalo, N.Y., May, 1994. Also, see, for example, U.S. Pat. Nos. 6,008,228; 6,100,277; and 6,245,806.
Some antiviral compounds that act as inhibitors of HIV replication are effective agents in the treatment of AIDS and similar diseases, e.g., azidothymidine or AZT. WO 99/67254 contains a discussion of AIDS and HIV protease inhibitors, and is incorporated herein by reference. However, a typical problem associated with retroviral protease inhibitors, like HIV protease inhibitors, has been the development of strains of the virus resistant to the inhibitor. The present invention provides nonpeptidic compounds that are effective inhibitors of HIV protease, and are useful in the treatment of AIDS or HIV infections, including multidrug-resistant strains of HIV.